With prostate cancer being ranked as the second leading cause of cancer related deaths in US men, it continues to pose a great challenge to public health. The androgen receptor (AR) plays an important part in the development and progression of prostate cancer. The AR mediates the response to androgens (hormones) such as dihydrotestosterone making it a validated drug target in prostate cancer and other human diseases. Prostate cancer is initially responsive to therapies that inhibit AR signaling, but the disease eventually advances to an androgen-independent state. In order to combat the progression of this disease, there is a need to identity new chemotherapeutic agents with novel mechanisms of action. The long-term objective of this project is to determine the molecular mechanism of chemoprevention by dibenzoylmethane (DBM). Dibenzoylmethane (DBM) is a minor constituent of licorice that is widely used in sunscreens as an ultraviolet blocking agent. In our laboratory, we have shown that DBM inhibits the proliferation of prostate cancer cells in vitro along with an accumulation of cells in the G1 phase of the cell cycle. The mechanistic basis for these antiproliferative effects are unknown. When the androgen-responsive LNCaP prostate cancer cells were exposed to DBM, we observed a loss in detection of the AR and an increase in expression of Hsp70 (an AR coactivator) by Western analysis in a dose dependent manner. There is evidence to suggest that progression of prostate cancer to metatasis or advanced disease may occur by alterations in interactions and expression between the AR and its coactivators. Western blot data was substantiated by our recent laboratory findings that DBM induced pronounced changes in the expression of Hsp70 by proteomic analysis. Experiments with positive outcomes have been done to test the effectiveness of DBM in the TRAMP mouse model of human prostate cancer and to evaluate its toxicity profile. In this present study, we attempt to advance toward elucidating the molecular basis for the antineoplastic effects of DBM in prostatic carcinoma cells by examining AR transactivation (signaling) through deregulation of AR interaction with its HSP complex.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Exploratory Grants (P20)
Project #
5P20MD000215-09
Application #
8128591
Study Section
Special Emphasis Panel (ZMD1)
Project Start
Project End
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
9
Fiscal Year
2010
Total Cost
$251,632
Indirect Cost
Name
Spelman College
Department
Type
DUNS #
069174407
City
Atlanta
State
GA
Country
United States
Zip Code
30314
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